Relaxin reduces endothelium-derived vasoconstriction in hypertension: Revealing new therapeutic insights.
- 作者列表："Leo CH","Ng HH","Marshall SA","Jelinic M","Rupasinghe T","Qin C","Roessner U","Ritchie RH","Tare M","Parry LJ
BACKGROUND AND PURPOSE:Endothelium-derived vasoconstriction is a hallmark of vascular dysfunction in hypertension. In some cases, an overproduction of endothelium-derived prostacyclin (PGI2 ) can cause contraction rather than relaxation. Relaxin is well known for its vasoprotective actions, but the possibility that this peptide could also reverse endothelium-derived vasoconstriction has never been investigated. We tested the hypothesis that short-term relaxin treatment mitigates endothelium-derived vasoconstriction in spontaneously hypertensive rats (SHR). EXPERIMENTAL APPROACH:Male Wistar Kyoto rats (WKY) and SHR were subcutaneously infused with either vehicle (20 mmol·L-1 sodium acetate) or relaxin (13.3 μg·kg-1 ·hr-1 ) using osmotic minipumps for 3 days. Vascular reactivity to the endothelium-dependent agonist ACh was assessed in vitro by wire myography. Quantitative PCR and LC-MS were used to identify changes in gene expression of prostanoid pathways and PG production, respectively. KEY RESULTS:Relaxin treatment ameliorated hypertension-induced endothelial dysfunction by increasing NO-dependent relaxation and reducing endothelium-dependent contraction. Notably, short-term relaxin treatment up-regulated mesenteric PGI2 receptor (IP) expression, permitting PGI2 -IP-mediated vasorelaxation. In the aorta, reversal of contraction was accompanied by suppression of the hypertension-induced increase in prostanoid-producing enzymes and reduction in PGI2 -evoked contractions. CONCLUSIONS AND IMPLICATIONS:Relaxin has region-dependent vasoprotective actions in hypertension. Specifically, relaxin has distinct effects on endothelium-derived contracting factors and their associated vasoconstrictor pathways in mesenteric arteries and the aorta. Taken together, these observations reveal the potential of relaxin as a new therapeutic agent for vascular disorders that are associated with endothelium-derived vasoconstriction including hypertension.
背景和目的: 内皮源性血管收缩是高血压血管功能障碍的标志。在某些情况下，内皮源性前列环素 (PGI2) 的过度产生可引起收缩而不是舒张。松弛素以其血管保护作用而闻名，但这种肽也可以逆转内皮源性血管收缩的可能性从未被研究过。我们检验了短期松弛素治疗缓解自发性高血压大鼠 (SHR) 内皮源性血管收缩的假设。 实验方法: 雄性 Wistar Kyoto 大鼠 (WKY) 和 SHR 皮下输注溶剂 (20 mmol · L-1 乙酸钠) 或松弛素 (13.3 μ g · kg-1 · hr-1) 使用渗透微量泵 3 天。通过线肌造影在体外评估血管对内皮依赖性激动剂 ACh 的反应性。定量 PCR 和 LC-MS 分别用于鉴定前列腺素类途径基因表达和 PG 产生的变化。 关键结果: 松弛素治疗通过增加 NO 依赖性舒张和减少内皮依赖性收缩改善高血压诱导的内皮功能障碍。值得注意的是，短期松弛素治疗上调肠系膜 PGI2 受体 (IP) 表达，允许 pgi2-ip 介导的血管舒张。在主动脉中，收缩逆转伴随着抑制高血压诱导的前列腺素生成酶增加和 PGI2 诱发的收缩减少。 结论和意义: 松弛素在高血压中具有区域依赖性血管保护作用。具体而言，松弛素对肠系膜动脉和主动脉的内皮源性收缩因子及其相关的血管收缩通路具有明显的作用。总之，这些观察结果揭示了松弛素作为一种新的血管疾病治疗药物的潜力，这些血管疾病与内皮源性血管收缩包括高血压有关。
METHODS:BACKGROUND:Hypertensive disorders of pregnancy (HDP) increase cardiovascular disease (CVD) risk. Pregnancy morbidities, including preeclampsia, and CVD are common in systemic lupus erythematosus (SLE). Possible connections are important to explore. In a population-based cohort, we investigated whether HDP is associated with a higher risk of cardiovascular outcomes separately in SLE and non-SLE to examine the role of SLE. METHODS:We identified first singleton births in the Medical Birth Register (1987-2012) among mothers with SLE and a large general population comparison group. Discharge diagnoses for HDP, cardiovascular outcomes, and hypertension in the Patient Register were identified using ICD codes. We estimated adjusted hazard ratios and 95% confidence intervals (HR, 95% CI) of the association between HDP and outcomes, in separate models in women with and without SLE. We then evaluated additive and multiplicative effect modification using relative excess risk due to interaction and Cox models jointly accounting for SLE and HDP, respectively. Mediation analysis estimated the proportion of the association between SLE and outcome explained by HDP. RESULTS:HDP were more common in SLE pregnancies (20% vs 7%). In SLE, HDP were associated with a two-fold higher rate of cardiovascular outcomes and three-fold higher rate of incident hypertension. HDP mediated 20% of the latter association. In women without SLE, HDP was associated with higher hypertension incidence later in life. CONCLUSION:In women with and without SLE, HDP were associated with a three-fold higher rate of hypertension. In SLE, women with HDP developed cardiovascular outcomes twice as often as women without HDP.
METHODS:BACKGROUND:'Neuronal precursor cell expressed developmentally down-regulated 4-like' (NEDD4L) is considered a candidate gene for hypertension-both functionally and genetically-through the regulation of the ubiquitination of the epithelial sodium channel (ENaC). This study explores the relationship between genetic variation in NEDD4L and hypertension with chronic kidney disease (CKD) in the southeastern Han Chinese population. METHODS:We recruited 623 CKD patients and measured ambulatory blood pressure monitoring (ABPM), and the rs4149601 and rs2288774 polymorphisms in NEDD4L were genotyped using qPCR. RESULTS:For rs4149601, significant differences in genotype frequencies in an additive model (GG vs GA vs AA) were observed between normotensive patients and hypertensive patients when hypertension was classified into ambulatory hypertension, clinical hypertension and ambulatory systolic hypertension (P = 0.038, 0.005 and 0.006, respectively). In a recessive model (GG+GA vs AA), the frequency of the AA genotype of rs4149601 in the hypertension groups were all higher than that in the normotensive groups. The genotype distribution of rs2288774 did not differ significantly between the normotensive and hypertensive patients. In both the full cohort and the propensity score matching (PSM) cohort, the AA genotype of rs4149601 (compared to the GG+GA genotype group) was independently correlated with ambulatory hypertension, clinical hypertension and ambulatory systolic hypertension by multivariate logistic regression analysis. CONCLUSIONS:The present study indicates that the AA genotype of rs4149601 associates with hypertension in CKD. Consequently, the rs4149601 A allele might be a risk factor for hypertension with CKD.
METHODS:BACKGROUND:The burden of hypertension in many low-and middle-income countries is alarming and requires effective evidence-based preventative strategies that is carefully appraised and accepted by key stakeholders to ensure successful implementation and sustainability. We assessed nurses' perceptions of a recently completed Task Shifting Strategy for Hypertension control (TASSH) trial in Ghana, and facilitators and challenges to TASSH implementation. METHODS:Focus group sessions and in-depth interviews were conducted with 27 community health nurses from participating health centers and district hospitals involved in the TASSH trial implemented in the Ashanti Region, Ghana, West Africa from 2012 to 2017. TASSH evaluated the comparative effectiveness of the WHO-PEN program versus provision of health insurance for blood pressure reduction in hypertensive adults. Qualitative data were analyzed using open and axial coding techniques with emerging themes mapped onto the Consolidated Framework for Implementation Research (CFIR). RESULTS:Three themes emerged following deductive analysis using CFIR, including: (1) Patient health goal setting- relative priority and positive feedback from nurses, which motivated patients to make healthy behavior changes as a result of their health being a priority; (2) Leadership engagement (i.e., medical directors) which influenced the extent to which nurses were able to successfully implement TASSH in their various facilities, with most directors being very supportive; and (3) Availability of resources making it possible to implement the TASSH protocol, with limited space and personnel time to carry out TASSH duties, limited blood pressure (BP) monitoring equipment, and transportation, listed as barriers to effective implementation. CONCLUSION:Assessing stakeholders' perception of the TASSH implementation process guided by CFIR is crucial as it provides a platform for the nurses to thoroughly evaluate the task shifting program, while considering the local context in which the program is implemented. The feedback from the nurses informed barriers and facilitators to implementation of TASSH within the current healthcare system, and suggested system level changes needed prior to scale-up of TASSH to other regions in Ghana with potential for long-term sustainment of the task shifting intervention. TRIAL REGISTRATION:Trial registration for parent TASSH study: NCT01802372. Registered February 27, 2013.